Thyroid disease represents a significant medical and public health challenge in the United States affecting over 19 million Americans. Hypothyroidism (HT) found in 4.6% of the US population, is increasingly common in the elderly affecting more than 20% of women and 11% of men. Hypothyroidism is defined by an elevated serum thyroid stimulating hormone (TSH) concentration with low serum thyroxine (T4) and tri- iodothyronine (T3) concentrations. Population studies demonstrate an age-related elevation in TSH concentrations, but at present, there is no consensus regarding the TSH concentration at which replacement therapy should be initiated. Another significant gap in knowledge is a lack of pharmacokinetic data of levothyroxine specifically in aging. The presence of endogenous thyroxine makes it impossible to differentiate between internally and externally-derived thyroxine using conventional laboratory tests. In Aims 1 we will conduct pharmacokinetic studies of 13C-LT4 in the elderly. We have designed and validated this method, using state-of- the-art technology, which permit the measurement of exogenous LT4 and conduct pharmacokinetic studies of single dose oral LT4 replacement. A secondary aim (Aim 2) will examine the bioactivity of TSH, assuming the age-related elevation in TSH concentrations consists of relatively more inactive TSH. Aim 3 will examine age-related thyroid hormone activity in peripheral tissues reflecting drug effectiveness. Our experience in patient recruitment and conducting PK studies using state-of-the- art liquid chromatography tandem mass spectrometry (LC/MS/MS) at Georgetown University Medical Center (GUMC), as well as our preliminary data, assure the success of this proposal. If the goals of this research are achieved it will advance the knowledge in the field and have a major impact on the aging population; with the aging of America's baby boomers the need to fully understand the progression thyroid disease, to improve diagnosis and treatment is vitally important to our nation and to our healthcare systems. We believe that these unique and innovative studies will provide a wealth of information that will translate to improved diagnosis, evaluation and management of therapeutic interventions.